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Prevention and Management

of Viral Hepatitis in Pregnancy

Article in Obstetrics and Gynecology Clinics of North America November

2014
DOI: 10.1016/j.ogc.2014.08.004

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Martha W F Rac
University of Texas Southw
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P re v e n t i o n a n d
Management of Viral
H e p a t i t i s i n Pre g n a n c y
Martha W.F. Rac, MD*, Jeanne S. Sheffield, MD

KEYWORDS
 Hepatitis A  Hepatitis B  Hepatitis C  Hepatitis D  Hepatitis E  Viral hepatitis
 Pregnancy

KEY POINTS
 Hepatitis A virus infection is an acute self-limiting infection with a benign course during
pregnancy.
 Hepatitis B virus (HBV) infection can cause both acute and chronic hepatitis. Although
HBV does not seem to adversely affect pregnancy outcomes, vertical transmission is a
risk that is significantly reduced by immunoprophylaxis of the newborn.
 Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United
States. Vertical transmission seems to be related to degree of maternal viremia, and ef-
forts for vaccine development are promising.
 Hepatitis D virus (HDV) requires coinfection with HBV for propagation, and tends to have a
more rapid progression to cirrhosis despite suppressing HBV viremia. Prevention of HBV
is the mainstay of the prevention of HDV.
 Hepatitis E virus is the most common cause of acute hepatitis worldwide, and portends a
20% risk of maternal mortality during pregnancy. Two vaccines are available for at-risk
populations in China, but studies are needed in pregnant populations before widespread
use becomes viable.

HEPATITIS A
Introduction
Disease description
Hepatitis A virus (HAV) is a single-stranded 27-nm RNA picornavirus. HAV infection is
usually a self-limiting illness that does not lead to chronic infection, and HAV immu-
noglobulin G (IgG) provides lifelong immunity. The average incubation period is
4 weeks. The virus can be detected in blood and feces 10 to 12 days after initial infec-
tion. A person is most contagious 14 to 21 days before the onset of symptoms and

The authors report no conflicts of interest.

Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center,
5323 Harry Hines Boulevard, Dallas, TX 75390-9032, USA
* Corresponding author.
E-mail address: Martha.Rac@utsouthwestern.edu

Obstet Gynecol Clin N Am 41 (2014) 573592

http://dx.doi.org/10.1016/j.ogc.2014.08.004 obgyn.theclinics.com
0889-8545/14/$ see front matter 2014 Elsevier Inc. All rights reserved.
574 Rac & Sheffield

continues to be so 1 week after symptoms begin. Symptomatic infection depends on

age of acquisition. Approximately 10% of children who become infected are symp-
tomatic. In countries of high endemicity, clinical disease is rare, as greater than
90% of people are infected as children and become subsequently immune by adult-
hood. In countries of lower endemicity, symptomatic infection is seen in adolescents
and adults of high-risk groups, such as injection drug users, men having sex with
men, travelers to high-prevalence areas, and members of closed religious commu-
nities.1 As a result, HAV presents a significant economic burden to countries of low
prevalence, such as the United States.1
Early infection is characterized by malaise, fatigue, fever, anorexia, nausea, and
abdominal pain, followed by jaundice and dark urine.2,3 Symptoms usually last no
more than 2 months, but can persist or relapse up to 6 months after initial infection
in 10% to 15% of patients.4 Fulminant hepatitis occurs in 0.01% of cases. Liver func-
tion rapidly deteriorates, and fatality rates are high when this occurs.
Risk factors
Humans are the only reservoir for HAV. Transmission occurs via the fecal-oral route,
person-to-person contact, or contaminated food and water. Much less commonly,
cases have been reported after intravenous drug use, blood transfusion, and sexual
contact, although usually during the early stages of disease when HAV viral loads
are highest.3 Travel to endemic areas, household contacts of infected persons, and
day care and health care settings are all known risk factors, although up to half of pa-
tients have no identifiable risk factor.
Prevalence/incidence/mortality rates
The incidence of HAV varies according to the socioeconomic development of the area.
Globally approximately 1.4 million new cases of hepatitis A are diagnosed each year.1
In 2011, the overall incidence rate in the United States was 0.4 per 100,000 popula-
tion.5 Since the introduction of the HAV vaccine in 1995, the incidence has decreased
by 95% in the United States.6 Mortality from acute infection is less than 1% but can be
higher in the setting of preexisting liver disease.3,7
Clinical Outcomes (Pregnancy/Maternal/Fetal)
Acute HAV infection during pregnancy is rare. As a result, incidence during pregnancy
is difficult to ascertain. Most cases reported in the literature are those requiring hos-
pitalization and/or recorded in countries endemic for HAV where acute infection in
the adult population is low.2 For example, Elinav and colleagues2 found that only 13
of 79,458 pregnancies admitted to an Israeli hospital over a 25-year period were diag-
nosed with acute HAV. During the HAV epidemic in Tennessee from 1994 to 1995, only
4 of the 1700 cases reported were pregnant women.8
In general, maternal and fetal outcomes are excellent in developed nations. Preterm
birth has been associated with HAV infection in the second and third trimesters, in
addition to neonatal cholestasis.2,9 In the same series from Israel,2 the average gesta-
tional age at delivery in women with HAV was 34 weeks. When fever and hypoalbumi-
nemia (defined as albumin <30 g/L) was present, delivery was significantly earlier, at a
mean gestational age of 32 weeks.2 Hepatitis A is not teratogenic, and transmission to
a fetus antepartum, intrapartum, and postpartum via breast milk is rare.
Management
Diagnosis
Diagnosis requires serologic testing. The presence of HAV immunoglobulin M (IgM) is
diagnostic of acute infection and persists for several months. HAV IgG predominates
 Viral Hepatitis During Pregnancy 575

during the convalescence stage and provides lifelong immunity. The presence of total
anti-HAV antibody indicates past infection but does not differentiate between acute
and chronic infection. Anti-HAV IgG is also positive after HAV immunization.3

Prevention
Prevention of HAV includes active and passive immunoprophylaxis. The HAV vaccine
is available as a single-antigen vaccine or in combination with hepatitis B virus (HBV)
vaccine. Both vaccines contain inactivated virus and are safe for use during preg-
nancy. The single-antigen vaccine is given in 2 doses, 6 to 12 months apart. The com-
bination vaccine is approved for persons 18 years old and upward, and is given in 3
doses at 0-, 1-, and 6-month intervals. After 1 month, 94% to 100% of adults achieve
protective levels of IgG and 100% of persons achieve immunity after the second dose.
Equivalent immunogenicity is achieved with the combination vaccine. Protective
levels of anti-HAV IgG have been shown to persist for 20 years.3,7
Immune globulin is also available for postexposure prophylaxis. It is prepared from
pooled human plasma and is given as a 0.02 mL/kg dose within 2 weeks of exposure.
Vaccination with single-antigen hepatitis A vaccine is, however, the preferred prophy-
laxis for persons aged 12 to 40 years. If immune globulin is administered, HAV vaccine
should still be administered as soon as possible.3,7 HAV vaccine and immunoglobulin
have been shown to be equally effective in preventing HAV if given within 2 weeks of
exposure.10
Universal vaccination is not recommended.1,3,7 Instead, vaccination is recommen-
ded based on medical or behavioral risk factors. Medical indications for vaccination
include persons with chronic liver disease or those receiving clotting factor concen-
trates. Behavioral indications include illegal drug use, men having sex with men, or
travel to areas with medium to high endemicity. Occupational indications for vaccina-
tion include working with HAV in a research laboratory setting, including HAV-infected
primates. A list of countries where vaccination is recommended before travel is avail-
able at http://www.cdc.gov/travel/diseases.htm.3,7

Treatment
Management of HAV includes supportive therapy. Outpatient management is under-
taken in most cases. Hospitalization is recommended for intractable vomiting, en-
cephalopathy, coagulopathy, or severe debilitation. Nutrition should be maintained
and physical activity limited, with the upper abdomen protected from trauma. Close
contacts should receive immunoprophylaxis.3,7 In the rare case of active infection dur-
ing labor and delivery, appropriate infectious disease precautions should be under-
taken with notification of the neonatologist to possible exposure of the infant.
Vaginal delivery is not contraindicated. Although HAV RNA has been documented in
the breast milk, no cases of vertical transmission have been reported, so breastfeed-
ing is not contraindicated.11

Complications and Concerns

As already stated, pregnancy outcomes with HAV are generally good. Fulminant he-
patic failure complicates fewer than 1% of acute HAV cases and has been reported
during pregnancy. In 2012, Simsek and colleagues12 reported on a patient at 18 weeks
of gestation who presented with acute hepatic failure, encephalopathy, and positive
HAV serologies. She underwent a liver transplant with histology positive for acute
necrotizing hepatitis A. Although the pregnancy was complicated by severe mid-
trimester oligohydramnios necessitating termination, she had an otherwise uneventful
recovery.
576 Rac & Sheffield

Summary
HAV is an acute, self-limiting infection that does not result in chronic infection. It is
endemic in developing countries where greater than 90% of adults have evidence
of past infection. By contrast, epidemics can occur in industrialized countries where
improved sanitation results in most adults being susceptible. The main route of trans-
mission is fecal-oral spread. Incidence during pregnancy is low, and mortality from
fulminant hepatic failure is rare. Preterm birth has been documented after infection
in the second and third trimester. Diagnosis is established with serologic testing for
HAV IgM and IgG. Routine obstetric management is recommended, and breastfeed-
ing is not contraindicated. HAV vaccine is safe during pregnancy and is recommended
based on medical, occupational, and lifestyle risk factors. Postexposure prophylaxis
includes immune globulin in addition to HAV vaccination, both of which offer equal
protection if given within 2 weeks after exposure.

HEPATITIS B VIRUS
Introduction
Disease description
HBV is a double-stranded DNA virus and a member of the Hepadnaviridae family. This
virus preferentially infects liver cells but can also be found in kidney, pancreas, and
mononuclear cells, although to a much lesser degree.1316 Hepatocellular injury is
thought to result from the host immune response to viral antigens and not from
DNA replication directly.17 Hepatitis B can cause both acute and chronic hepatitis.
Risk factors
Transmission occurs via parental or mucosal exposure to infected body fluids. Con-
centrations are higher in blood and serous fluids than those found in semen and
saliva.18 In low-prevalence countries (prevalence <2%) such as the United States,
sexual contact is the major route of transmission. In countries endemic for HBV (prev-
alence 8%15%), perinatal exposure accounts for most transmissions.19,20 As a
result, pregnancy poses a particular opportunity to affect the epidemiology of HBV.
Prevalence/incidence/mortality rates
Each year HBV affects 350 million people worldwide. In the United States, an esti-
mated 800,000 to 1.4 million people are living with hepatitis B. Since the implementa-
tion of routine childhood vaccination in 1990, the rate of acute hepatitis B in the United
States has declined 82%,20 and in 2011 the national rate of HBV was 0.9 per 100,000
population. The risk of developing chronic hepatitis B is inversely related to age at
infection, with 90% of infants, 30% of children younger than 5 years, and only 2%
to 6% of those infected as adults progressing to chronic disease.3 Of those who
develop chronic HBV, 15% to 40% will develop severe complications including
cirrhosis, liver failure, and hepatocellular carcinoma.21 As a result, it is estimated
that hepatitis B contributes to 786,000 deaths worldwide each year.22

Clinical Outcomes (Pregnancy, Maternal, Infant)

The course of HBV in pregnancy is similar to that in the general population. The incu-
bation period ranges from 6 weeks to 6 months (average 75 days), and only 50% of
infected persons will be symptomatic.20,22 Symptomatic disease includes nausea,
vomiting, abdominal pain, fatigue, and jaundice. The risk of fulminant hepatic failure
and death after acute infection is approximately 1%.22
Despite earlier evidence suggesting increased maternal morbidity and mortality,
recent evidence from large population-based cohorts suggest that pregnancy is not
 Viral Hepatitis During Pregnancy 577

significantly affected by HBV.23,24 Reddick and colleagues24 reviewed 297,664 preg-

nancies from the Nationwide Inpatient Sample and found a slight increase in preterm
birth (adjusted odds ratio 1.65, 95% confidence interval 1.32.0) but no association
with intrauterine growth restriction or preeclampsia. In 2011 Connell and colleagues23
reviewed 1,670,369 records and found no increase in adverse pregnancy outcomes in
women with HBV, but rather a decreased risk of babies being small for gestational
age.

Management
Diagnosis
The diagnosis of HBV is based on laboratory testing. Fig. 1 illustrates the pattern of
the varying HBV antigens and antibodies in acute infection. Hepatitis B surface anti-
gen (HBsAg) and hepatitis e antigen (HBeAg) appear first, followed by IgM antibody to
hepatitis B core antigen. This combination of antigens and antibodies is characteristic
of acute infection. The presence of IgG anticore or IgG antisurface indicates resolving
or past infection. IgG antisurface is also positive in vaccinated persons and is evi-
dence of lifelong immunity.22 Persistence of HBsAg greater than 6 months signifies
chronic infection, and HBeAg indicates ongoing viral replication and infectivity
regardless of time from initial infection (Table 1). Women positive for HBsAg are
considered infected, and should have HBeAg and HBV viral load sent to guide man-
agement and counseling. This strategy, in combination with maternal antiviral treat-
ment if positive, has been found to be cost-effective in the prevention of perinatal
infection.25
The American College of Obstetricians and Gynecologists (ACOG), the Centers for
Disease Control and Prevention (CDC), the World Health Organization (WHO), and the
US Preventive Services Task Force recommend universal screening of all pregnant

Fig. 1. Serologic response to acute hepatitis B Virus. ALT, alanine aminotransferase; anti-
HBc, antibody to hepatitis B core antigen; anti-HBe, antibody to hepatitis B e antigen;
anti-HBs, antibody to hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HBsAg, hep-
atitis B surface antigen; IgG, immunoglobulin G; IgM, immunoglobulin M. (Adapted from
Dienstag JL. Acute viral hepatitis. In: Longo DL, Fauci AS, Kasper DL, et al, editors. Harrisons
principles of internal medicine, 18th edition. New York: McGraw-Hill; 2012. p. 2540.)
578 Rac & Sheffield

Table 1
Interpretation of serologic test results for hepatitis B virus

Serologic Marker
HBsAg Total Anti-HBc IgM Anti-HBc Anti-HBs Interpretation
Never infected
1 Early acute infection or first 18 d after
vaccination
1 1 1 Acute infection
1 1 Acute infection but resolving
1 1 Chronic infection
1 1 Immune from past infection
1 Post HBV vaccination
1 False positive; low-level chronic infection
or passive transfer to infant born to
HBsAg-positive mother

Abbreviations: Anti-HBc, antibody to hepatitis B core antigen; Anti-HBs, antibody to HBsAg;

HBsAg, hepatitis B surface antigen; IgM, immunoglobulin M.
Adapted from Centers for Disease Control and Prevention. Sexually transmitted disease treat-
ment guidelines 2010. MMWR Recomm Rep 2010;59(RR-12):1110.

women using HBsAg.3,7,20,26 In a recent retrospective review of all pregnancies

infected with HBV from 2007 to 2011 in a single United Kingdom hospital, 71% of
mothers were first diagnosed during pregnancy.27 Thus, pregnancy provides a unique
opportunity for screening and identification of HBV in a population that serves as a
viral reservoir for future generations.

Treatment
Treatment of acute hepatitis B during pregnancy is mainly supportive. As already
stated, vertical transmission is more likely if acute hepatitis B occurs during the third
trimester.28 After acute infection, 85% to 90% of adults clear the virus and the remain-
ing 10% to 15% develop chronic infection. Treatment of chronic hepatitis B outside of
pregnancy depends on the level of viremia, presence of HBeAg, and degree of liver
injury determined by either transaminase levels or liver histology.29 Most women dur-
ing pregnancy are in the immune-tolerant stage (elevated HBV viral load but normal
transaminases). However, certain situations arise whereby antiviral treatment is
considered. If pregnancy occurs while on treatment, discontinuation of antiviral medi-
cation has been associated with rebound hepatitis and liver decompensation.30 Simi-
larly, antiviral therapy is considered if the woman is newly diagnosed and found to
have cirrhosis. However, the main role of antiviral therapy during pregnancy is as
prophylaxis against vertical transmission.
Intrapartum management of HBsAg-positive mothers generally does not deviate
from routine obstetric management. Although no studies have been performed eval-
uating the impact of invasive fetal monitoring on vertical transmission rates, it seems
reasonable to avoid based on theoretic risks. When preterm premature rupture of
membranes (PPROM) complicates antenatal care of seropositive women, pregnancy
prolongation can be undertaken, as fetal exposure to HBV-positive maternal fluids and
maternal-fetal microtransfusion remain low in the absence of active labor.31
It has been hypothesized that elective cesarean delivery might have an advantage
over vaginal delivery in terms of vertical transmission rates because fetal exposure
 Viral Hepatitis During Pregnancy 579

to maternal blood and body fluids is minimized before the onset of labor or rupture of
membranes. A recent retrospective review from China found that of the 1409 infants
born of HBV-seropositive women, vertical transmission occurred only when the
maternal viral load exceeded 106. Elective cesarean delivery was associated with a
lower vertical transmission rate (1.6%) when compared with vaginal delivery (3.6%)
or urgent cesarean delivery (4.6%) despite adequate neonatal immunoprophylaxis,
leading the investigators to conclude that in mothers with high viral loads, elective ce-
sarean delivery might be associated with lower rates of vertical transmission.32 By
contrast, other studies have found that elective cesarean delivery is not protective.
More evidence is needed before a change is made to current recommendations
regarding route of delivery.7
During the postpartum period, transmission can occur through direct contact with
infected household members and, rarely, via breastfeeding.33 The ACOG and the
CDC do not discourage breastfeeding in infants who have received appropriate immu-
noprophylaxis.7,28 Exceptions include women receiving antiviral therapy, as limited
data are available regarding drug excretion into human breast milk.34

Prevention
Prevention of mother-to-child-transmission can occur at both the maternal and
neonatal level. The US Food and Drug Administration (FDA) has approved 2 products
for prevention of hepatitis B: hepatitis B immune globulin (HBIG), and the hepatitis B
vaccine. Routine vaccination is recommended for high-risk populations, which include
persons with multiple sex partners, men who have sex with men, intravenous drug
users, health care workers, those coinfected with other sexually transmitted diseases,
members of correctional facilities and/or drug treatment centers, or those in direct
contact with an HBV-positive household member.3 The hepatitis B vaccine contains
recombinant HBsAg prepared from yeast cultures. It is safe in pregnancy and during
breastfeeding. Three sequential injections are required for complete serologic protec-
tion, traditionally given at an interval of 0, 1, and 6 months. However, this dosing inter-
val may be difficult to complete during pregnancy.7 Sheffield and colleagues35 showed
that an accelerated dosing schedule at 0, 1, and 4 months resulted in improved rates
of completion and a 90% seroconversion rate after 3 doses.
HBIG is composed of plasma from pooled donors with high concentrations of anti-
HBs IgG. If used alone for postexposure prophylaxis, protective levels of antibodies
last 3 to 6 months.36,37 Most commonly it is given as an adjunct to the HBV vaccine.
In the neonate, passive-active immunoprophylaxis of the infant with HBIG and the
hepatitis B vaccine has been shown to be 95% effective for preventing neonatal infec-
tion if given within 12 to 24 hours after delivery.38
In mothers with high HBV viremia (>106 copies per mL), treatment with antiviral
medication initiated in the third trimester has been shown to decrease the rate of ver-
tical transmission to the newborn. No consensus exists on which antiviral is best for
this indication. Lamivudine, a cytidine nucleoside analogue, is the most studied anti-
viral during pregnancy given its use in human immunodeficiency virus (HIV) infection,
and has a reassuring safety profile. In a systematic review of 10 randomized controlled
trials, Shi and colleagues39 found that initiating lamivudine at 28 to 32 weeks of gesta-
tion had a 1.4% to 2.0% lower transmission rate without higher complications rates.
Telbivudine is another option in the same drug class with similar efficacy but with
less resistance than lamivudine.40 Tenofovir disoproxil fumarate (TDF) is a class B
medication that has also been used for prevention of vertical transmission of HBV.
Although data are limited in HBV-positive pregnancies, TDF use in the third trimester
has shown a benefit without adverse effects on pregnancy.41,42 In addition, HBIG
580 Rac & Sheffield

given in the third trimester to women with high viremia reduces vertical transmission.39
Both antiviral therapy and HBIG given to the mother antenatally have been shown to
be cost-effective.43

Complications and Concerns

Maternal viremia, one of the strongest risk factors for vertical transmission, is
measured directly using the level of HBV DNA or indirectly by the presence of HBeAg,
a viral protein synthesized in concordance with HBV DNA transcription.28 Even in the
presence of adequate neonatal immunoprophylaxis, there is a 8% to 10% failure rate
in HBeAg-positive mothers with high levels of HBV DNA.41,44 Transmission rates to the
neonate are lower in this high-risk group for those women receiving antiviral therapy
during the third trimester.39,41,42
Vertical transmission can occur antepartum, intrapartum, or postpartum. In acute
hepatitis B infection during the first trimester, 10% of infants will become infected,
compared with 80% to 90% when acute infection occurs during the third trimester.28
Amniocentesis is not contraindicated in HBV-positive gravidas. In 1999, Alexander
and colleagues45 found that none of the 21 infants whose mothers were chronic
HBV carriers and underwent midtrimester amniocentesis tested positive for HBsAg
during the first year of life. By contrast, more contemporary evidence taking into ac-
count the level of maternal viremia found that the vertical transmission rate after mid-
trimester amniocentesis was significantly higher when the maternal viral load
exceeded 107 copies/mL.46 Although more evidence is needed to change current rec-
ommendations, the level of maternal viremia should be taken into account before pro-
ceeding with any invasive antepartum procedure.

Summary
HBV is a double-stranded DNA virus that affects 350 million people worldwide. Trans-
mission occurs via parental or mucosal exposure to infected body fluids. In countries
endemic for HBV, perinatal transmission is the major route of infection. All pregnant
women should be tested for HBV at least once during pregnancy. Infection is marked
by the presence of HBsAg. If positive, HBeAg and HBV DNA level should be obtained
for management planning and patient counseling. Risk of perinatal infection without
infant immunoprophylaxis is 10% and rises to 80% when HBeAg is present. Level
of maternal viremia also influences vertical transmission rates, with viral loads greater
than 106 associated with higher rates of perinatal infections. It is unclear if elective ce-
sarean delivery reduces vertical transmission rates. Breastfeeding is not contraindi-
cated. Treatment of HBV during pregnancy is mainly supportive. HBV vaccine is
recommended for high-risk groups and can be administered at 0, 1, and 6 months
or via an accelerated schedule of 0, 1, and 4 months with equal efficacy. All infants
born to HBV-positive mothers should receive HBIG and HBV vaccine within 24 hours
of birth. Maternal antiviral therapy starting at 28 to 32 weeks has been shown to
reduce rates of perinatal infection without adverse effects.

HEPATITIS C
Introduction
Disease description
Hepatitis C is the most common blood-borne infection in the United States. Hepatitis
C virus (HCV) is an RNA virus from the Flaviviridae family47 and possesses an error-
prone RNA replicase, which is responsible for the genetic heterogeneity between
the 6 major HCV genotypes. Genetic diversity of HCV has complicated antiviral
 Viral Hepatitis During Pregnancy 581

therapy and is one of the main reasons why seroconversion does not provide lifelong
immunity.48 Genotype 1 accounts for most infections in the United States.

Risk factors
Hepatitis C is a blood-borne infection, and transmission most commonly occurs
through exchange of infected blood and body fluids. Populations at highest risk
include intravenous drug users (IVDU) and those receiving infected blood products.49
It is estimated that 60% to 80% of IVDU are infected with hepatitis C. Since screening
of blood products began in 1992, the risk of acquiring HCV after a blood transfusion is
now estimated to be 1 in 2 million transfusions.50 Transmission less commonly occurs
perinatally or through sexual contact.3 Both HIV coinfection and numerous sexual
partners increases the likelihood of sexual transmission.3

Prevalence/incidence/mortality rates
It is estimated that greater than 4.8 million people are chronically infected in North
America, a prevalence rate of 1.3%.49 The incidence of HCV during pregnancy is
1% to 2.4%.7 Of infants born to seropositive women, 6 in 100 will acquire HCV peri-
natally,50,51 translating into almost 2500 perinatally acquired infections annually.

Clinical Outcomes (Pregnancy, Maternal, Fetal)

Most HCV infections are asymptomatic and are discovered either from screening
high-risk groups or during evaluation of persistent transaminitis. Symptoms of abdom-
inal pain, nausea, vomiting, and fatigue can develop 1 to 3 months after infection.
Jaundice occurs in 10% to 15% of acute infections, and has been shown to correlate
with clearance of acute infection.48 Severe acute disease leading to hepatic failure is
rare. Up to 85% of patients develop chronic HCV. Progression to cirrhosis is related to
the patients age at initial infection in addition to alcohol consumption and degree of
immunosuppression.5254 HCV RNA can be detected in blood 1 to 3 weeks after initial
infection, and seroconversion occurs by 6 months.3
Most HCV infected pregnant women have chronic disease. It was previously
thought that HCV had limited effects on pregnancy. However, recent reports have
shown an association with intrahepatic cholestasis of pregnancy, gestational dia-
betes, and preterm delivery in seropositive gravidas.23,24,55,56 Adverse fetal outcomes
reported include an increased incidence of congenital anomalies, low birth weight,
newborns small for gestational age, need for assisted ventilation, and requirement
of neonatal intensive care.23 Most recent data suggest that HCV seropositivity during
pregnancy is associated with an adverse neurologic outcome, cephalohematoma,
fetal distress, feeding difficulties, intraventricular hemorrhage, and neonatal seizure.57

Management
Diagnosis
Routine prenatal screening is not recommended. The CDC and the ACOG recommend
risk-based testing during pregnancy to include women with past or current intrave-
nous drug use, HIV positivity, history of blood transfusion and/or solid organ transplant
before 1992, history of having received clotting factor concentrates before 1987, un-
dergoing long-term dialysis, signs/symptoms of liver disease, and seeking treatment
at STD clinics.3,7 Antibody to HCV, using either a second-generation or third-
generation enzyme immunoassay, is used for screening. Seroconversion may not
be evident for 6 to 10 weeks after acute infection; therefore if anti-HCV is negative
but clinical suspicion remains high, HCV RNA using polymerase chain reaction can
be detected soon after initial infection.7
582 Rac & Sheffield

Most patients during pregnancy who test positive for antibody to HCV have
chronic disease. Quantification of HCV RNA is useful for patient counseling, as
high levels of maternal viremia have been associated with higher rates of vertical
transmission.58 Although human leukocyte antigen variations and mismatches be-
tween the mother and her infant have been shown to be prognostic in terms of ver-
tical transmission rates,59 genetic testing is currently not recommended. Full
evaluation of liver function, presence of cirrhosis, and presence of other organ sys-
tem dysfunction is warranted for both staging and prognosis. Liver biopsy is usually
deferred until after delivery.

Prevention
Unlike HBV, no vaccine or immunoprophylaxis is available for HCV-positive women or
their neonates. Rates of transmission have been shown to be as low as 0% to 3%
when maternal HCV RNA was undetectable.51,58,60 Women who are HCV negative
but remain at high risk of acquisition should be educated regarding practices that
decrease the risk of transmission.3 Because the risk of sexual transmission is low,
serodiscordant monogamous couples do not need to change their sexual practices,
but should be tested regularly.3 HCV disease is not a contraindication to
breastfeeding.

Treatment
The preferred treatment of chronic HCV is a combination of pegylated interferon and
ribavirin, both of which are contraindicated during pregnancy. Ribavirin has been
shown to be teratogenic and pegylated interferon has been shown to have adverse ef-
fects on fetal growth.61 Newer treatment options include direct-acting antivirals, which
target specific steps in the HCV viral replication cycle. These agents have less
morbidity than nonspecific therapy, and shorter treatment times.49,62,63 However, their
safety during pregnancy has not been established, and studies are needed before rec-
ommending treatment with these antivirals. Seropositive women with systemic com-
plications from HCV should be comanaged by both maternal-fetal medicine
specialists and gastroenterologists specializing in viral hepatitis.
The mode of delivery has not been shown to affect vertical transmission rates for
HCV-positive women.51,64 Invasive procedures, such as fetal scalp electrode or fetal
scalp sampling, should be avoided, as these procedures have been shown to in-
crease vertical transmission rates.58 Evidence is lacking regarding the risk of trans-
mission after amniocentesis, although no evidence suggests an increased risk.65 If
amniocentesis is performed, traversing the placenta should be avoided. Vertical
transmission has been shown to be higher after premature rupture of membranes.
However, this could be related to maternal viral load and length of membrane
rupture. Recent data from Japan noted that in women with high viral loads (defined
as >6  105 IU/mL), delivery 4 or more hours after membrane rupture was associ-
ated with a significantly higher rate of infected infants.66 Further studies are needed
before recommendations can be made as regards management of PPROM in sero-
positive pregnancies. Breastfeeding does not seem to increase transmission rates,
and is therefore not contraindicated unless the nipples are cracked and/or
bleeding.3,67

Complications and Concerns

Vertical transmission can occur at any time during gestation. One-third of transmis-
sions occur antepartum, 40% to 50% occur peripartum, and transmission during
the postpartum period is rare.68 Risk appears to be greatest in women with an
 Viral Hepatitis During Pregnancy 583

RNA viral load greater than 2.5  106 RNA copies/mL58 and those with HIV coinfec-
tion. Vertical transmission can be as high as 15% to 25% in women with coincident
HIV.58 Although highly active antiretroviral therapy reduces HIV transmission to the
neonate, it remains unclear whether HCV vertical transmission is similarly
affected.69

Summary
HCV is the most common blood-borne infection in the United States. Approximately
1.2 million people, including 1% to 2.4% of pregnant women, are chronically infected.
Risk factors include intravenous drug use and blood/body fluid contact. Most acute
infections are asymptomatic, and 85% of infected patients develop chronic disease
with the potential for cirrhosis and hepatocellular carcinoma. Retrospective reviews
have reported an increase in preterm birth, low birth weight, neonates small for gesta-
tional age, requirement of neonatal intensive care, congenital anomalies, and adverse
neurologic outcomes in HCV-positive mothers, although outcomes are generally
favorable. There is no vaccine for HCV. Testing during pregnancy is recommended
for high-risk patients. Treatment during pregnancy is supportive, and invasive proce-
dures should be avoided. Perinatal transmission is not influenced by mode of delivery,
but does appear to be increased with high maternal viremia and HIV coinfection.
Breastfeeding is not contraindicated. HCV-positive women should have long-term
follow-up conducted by a hepatologist.

HEPATITIS D
Introduction
Disease description
Hepatitis D virus (HDV) is a small, incomplete RNA virus that requires the HBsAg coat
for both transmission and replication. Therefore, monoinfection with HDV does not
occur.70 Coinfection with HBV is associated with more severe acute hepatitis. Pro-
gression to cirrhosis occurs in 70% to 80% of patients with chronic disease. In
15%, progression occurs within 2 years.7,71,72 Similarly to HBV, transmission of
HDV occurs through contact with infected blood/body fluids or blood products.72

Risk factors
Risk factors for acquiring HDV are similar to those specific to HBV (see earlier discus-
sion in the hepatitis B section under Risk Factors). Patients not immunized against
HBV are also susceptible to HDV coinfection.72

Incidence/prevalence/mortality rates
It is estimated that 15 million of the 350 million individuals with chronic HBV have also
been exposed to HDV.70 Areas endemic for HBV have the highest rates of HDV infec-
tion.73 Mortality rates after HDV/HBV coinfection are 10 times higher than those for
HBV monoinfection.72 The true incidence of HDV during pregnancy is unknown, as es-
timates quoted in the literature originate from countries where HBV is endemic.7476 In
a recent study from Africa, 14.7% of HBV-positive gravidas were coinfected with
HDV.74

Clinical Outcomes (Pregnancy, Maternal, Infant)

Pregnancy outcomes specific to women with HBV/HDV coinfection have not been re-
ported. Although HBV DNA levels are lower in coinfected women, no evidence exists
to suggest better maternal or fetal outcomes.74
584 Rac & Sheffield

Management
Diagnosis
The WHO recommends that all women who are HBsAg positive or have evidence of
recent HBV infection72 be tested for HDV. The preferred method of diagnosis is detec-
tion of total anti-HDV antibodies. Presence of hepatitis D antigen and HDV RNA is ev-
idence of active liver disease.71,72 No cases of HDV reinfection have been reported.72

Prevention
There is no HDV-specific vaccine. Because HDV requires the presence of HBV for sur-
vival, all measures that prevent HBV will also prevent HDV (see section on hepatitis B).

Treatment
Treatment of HBV/HDV coinfection during pregnancy is supportive. Long-term pegy-
lated interferon therapy has yielded remissions, but is contraindicated during preg-
nancy. Because HDV lacks its own viral polymerase, oral nucleos(t)ides seem to
have little effect on HDV viral replication, and addition of these agents is indicated
solely for the treatment of HBV.7173 In the cases of fulminant hepatic failure and
end-stage liver disease, liver transplantation can be life-saving.

Complications and concerns

As already stated, coinfection with HDV causes more severe liver disease with faster
progression to cirrhosis and higher mortality rates in comparison with HBV monoinfec-
tion.73 However, rates of hepatocellular carcinoma are not higher with coinfection,
perhaps because of HDV suppression of HBV replication.77

Summary
HDV is an incomplete RNA virus that requires HBV for transmission and replication.
Approximately 15 million people with chronic HBV have evidence of exposure, mainly
in areas endemic for HBV. Liver disease is more severe and mortality rates are higher
in comparison with HBV monoinfection. Preventive measures against HBV also pre-
vent HDV coinfection. There is no HDV-specific vaccine, and treatment during preg-
nancy is supportive. Since the adoption of HBV immunoprophylaxis, perinatal
transmission of HDV has been rare.

HEPATITIS E
Introduction
Disease description
Hepatitis E virus (HEV) is a single-stranded, nonenveloped RNA virus that has histor-
ically been a disease of developing countries, similar to HAV. In recent years, an
increasing number of cases have emerged in more developed countries as a result
of zoonotic infections from infected, undercooked meats.78,79 There are 4 genotypes
known to infect humans. Genotypes 1 and 2 are endemic in Asia, Africa, Central Amer-
ica, and other developing countries where sanitation is poor. Humans are the only
known reservoir, and fecal-oral transmission occurs through water contamination. Ge-
notypes 3 and 4 are more prevalent in developed countries, such as the United States,
the United Kingdom, and Japan. These genotypes infect humans and animals, with
swine being the main reservoir. Zoonotic spread via consumption of raw or under-
cooked meat, namely pork or game, has been shown to be the main route of transmis-
sion in these countries.
Most HEV infections are asymptomatic. The incubation period ranges from 2 to
8 weeks and symptoms include myalgia, arthralgia, weakness, vomiting, jaundice,
 Viral Hepatitis During Pregnancy 585

itching, acolic stools, and dark urine. The symptomatic phase is accompanied by
elevated transaminases and jaundice.78,80,81 Most infections are self-limiting, but
chronic infection can develop in immunocompromised patients.82 When this occurs,
progression to cirrhosis is rapid and can occur 2 to 3 years after infection.71 One of
the features of HEV that most distinguish it from the other hepatides is its particularly
virulent course during pregnancy whereby mortality rates from fulminant hepatic fail-
ure are estimated to be 10- to 25-fold higher83,84; this is seen more frequently with
gentoypes 1 and 2. Extrahepatic manifestations of HEV include neurologic symptoms
in 2% to 5% of cases, in addition to glomerulonephritis or cryoglobulinemia.85,86

Risk factors
In endemic areas where sanitation is poor, HEV is acquired through contaminated
drinking water. In industrialized countries where genotypes 3 and 4 predominate,
infection mainly occurs from ingestion of infected meats, mainly pork or deer meat.
Feagins and colleagues87 found that 11% of pig livers obtained from grocery stores
in the United States contained HEV RNA. Cooking temperature greater than 70 C
for 20 minutes is necessary to inactivate the virus. Persons who have direct contact
with infected animals, such as pig handlers and/or veterinarians, are also at risk of
infection through infected water. Transmission can also occur through blood transfu-
sions and solid organ donations. Perinatal transmission of HEV during acute infection
has been documented,88 and the risk of transmission can be as high as 79%.89 How-
ever, this estimate is limited by small case series, limited surveillance, and underdiag-
nosis of HEV during pregnancy.

Prevalence/incidence/mortality rates
The prevalence of HEV IgG antibody is as high as 50% in endemic countries. Globally
there are an estimated 20 million cases of HEV reported each year, and more than 3
million are symptomatic. The overall mortality rate is less than 1%, with approximately
57,000 to 70,000 deaths each year.81,90 As HEV can be particularly virulent during
pregnancy, most deaths reported are in pregnant women. The WHO estimates that
the risk of death in the third trimester is 20%.81

Clinical Outcomes (Pregnancy, Maternal, Infant)

Most studies performed on HEV-infected pregnant populations were conducted in
countries of high endemicity. From these populations, where genotypes 1 and 2 pre-
dominate, pregnancy outcomes differ depending on severity of infection. High rates
of preterm delivery and perinatal mortality have been reported.91,92 A recent prospec-
tive study of 36 HEV-positive pregnant women in India found significantly higher rates
of encephalopathy (30.5%), coagulopathy (72.2%), and intrauterine demise (55.5%)
when compared with HBV-positive pregnancies. Further, all maternal deaths (n 5
5) occurred in HEV-positive women.93 Gravidas who experience acute liver failure
have worse pregnancy outcomes than those who have only acute hepatitis. Borka-
koti and colleagues94 found a 56% death rate in pregnant women with acute hepatic
failure, compared with 0.9% in those with acute HEV hepatitis. Gravidas with acute
HEV liver failure also had significantly higher rates of intrauterine death (78.6% vs
11.4%), preterm delivery (65.7% vs 17.3%), and maternal mortality (56.2% vs
0.9%). The question as to why HEV has such a virulent course during pregnancy re-
mains to be answered. Elevated levels of tumor necrosis factor a and cytokine gene
polymorphisms have been found in HEV-positive pregnant women in comparison
with nonpregnant populations.95,96 Viral load seems to play a factor, at least indi-
rectly. Women with HEV during pregnancy have higher viral loads that are
586 Rac & Sheffield

proportional to disease severity.92,94 Studies of pregnancy outcomes in industrial-

ized, nonendemic countries are lacking. In a recent study from France, HEV seropre-
valence during pregnancy was unexpectedly high (29.3%) in contrast to the lack of
symptomatic disease, suggesting that most infection during pregnancy was subclin-
ical or asymptomatic.97
Vertical transmission of HEV has been reported, and can occur at any point during
pregnancy. Reported transmission rates are as high as 67% in women with symptom-
atic infection.88 Unlike HBV or HCV, HEV is often self-limited in the neonate. Progres-
sion to fulminant hepatitis is rare.88 No studies have evaluated whether HEV can be
transmitted through breastfeeding, so recommendations are lacking.88
Management
Diagnosis
It is difficult to distinguish HEV from other forms of acute hepatitis, so a high degree of
suspicion is warranted. Testing is indicated in any patient with unexplained hepatitis
regardless of age or travel history.81 Diagnostic markers of infection include HEV
RNA, HEV IgM, and HEV IgG. If HEV IgM or IgG are positive, confirmatory testing
with HEV RNA should be ordered. Serology can be falsely negative in immunocompro-
mised patients; therefore, HEV RNA testing is recommended if clinically suspected in
this population.71 Persistently positive HEV RNA and rising IgG titers are characteristic
of chronic infection.71,84 HEV IgG does not confer protective immunity.84
Prevention
There is no FDA-approved vaccine against HEV.81 However, 2 different recombinant
vaccines have been developed that show high efficacy against HEV.83 Though prom-
ising, more data are needed in pregnant populations before widespread immunization
is recommended. Other preventive measures include avoiding use or consumption of
water of unknown purity, especially in areas endemic for HEV. Such measures include
use of bottled water and avoidance of food cleaned with local water.81 In countries
where genotypes 3 and 4 predominate, meats should be cooked at temperatures
higher than 70 C for at least 20 minutes to inactivate the virus.84
Treatment
Treatment of HEV during pregnancy is supportive. Ribavirin (and in some instances
pegylated interferon) has been used in nonpregnant populations to assist viral clear-
ance, but is contraindicated during pregnancy.84 The main treatment of HEV is through
prevention (see earlier discussion).
Complications and Concerns
Hepatitis E causes a disproportionate number of deaths during pregnancy from acute
liver failure in developing countries. Prevention can be achieved through good hygiene
practices and improved sanitation, and clinical trials of vaccine efficacy are promising.
Summary
HEV is the most common cause of acute hepatitis worldwide. Genotypes 1 and 2 are
common in developing countries where sanitation and water purity is poor, making
fecal-oral transmission the main route of acquisition. Acute viral hepatitis with fulmi-
nant hepatic failure and death are distinguishing features during pregnancy, with a
20% risk of maternal mortality during the third trimester. Other adverse pregnancy out-
comes include preterm delivery, intrauterine death, and vertical transmission. Geno-
types 3 and 4 predominate in industrialized countries, and the main route of
transmission is through undercooked meats from infected animals, mainly pork. The
 Viral Hepatitis During Pregnancy 587

disease course of HEV during pregnancy is much less virulent. HEV is usually self-
limited, but can become chronic in immunocompromised patients. Diagnosis is
made by identification of HEV IgM and/or IgG and is confirmed by the presence of
HEV RNA. Treatment is supportive. Although no vaccines have been approved for
use in the United States, there are 2 vaccines currently available to at-risk populations
in China. Further studies of pregnant patients are needed before universal vaccination
is recommended.

REFERENCES

HEPATITIS A

1. World Health Organization. Available at: http://www.who.int/mediacentre/

factsheets/fs328/en/. Accessed April 28, 2014.
2. Elinav E, Ben-Dov IZ, Shapira Y, et al. Acute hepatitis A infection in pregnancy is
associated with high rates of gestational complications and preterm labor.
Gastroenterology 2006;130:112934.
3. Centers for Disease Control. Sexually transmitted disease treatment guidelines
2010. MMWR Recomm Rep 2010;59(RR-12):1110.
4. Dienstag JL. Acute viral hepatitis. In: Longo DL, Fauci AS, Kasper DL, et al,
editors. Harrisons principles of internal medicine. 18th edition. New York:
McGraw-Hill; 2012. p. 253757.
5. Centers for Disease Control and Prevention. Division of Viral Hepatitis. Viral
hepatitis statistics and surveillance surveillance for viral hepatitis, United States
2011. Available at: http://www.cdc.gov/hepatitis/Statistics/2011Surveillance/
Commentary.htm#hepA. Accessed April 28, 2014.
6. Centers for Disease Control and Prevention. Hepatitis A information for health pro-
fessionals. Available at: http://www.cdc.gov/hepatitis/HAV/HAVfaq.htm#general.
Accessed May 23, 2014.
7. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin
No. 86: Viral hepatitis in pregnancy. Obstet Gynecol 2007;110:94155 Reaffirmed
2012.
8. Willner IR, Howard SC, Williams EQ, et al. Serious hepatitis A: an analysis of pa-
tients hospitalized during an urban epidemic in the United States. Ann Intern Med
1998;128:1114.
9. Urganci N, Arapoglu M, Akyildiz B, et al. Neonatal cholestasis resulting from
vertical transmission of hepatitis A infection. Pediatr Infect Dis J 2003;22(4):
3812.
10. Victor JC, Monto AS, Surdina TY, et al. Hepatitis A vaccine versus immune glob-
ulin for postexposure prophylaxis. N Engl J Med 2007;357(7):168594.
11. Daudi N, Shouval D, Stein-Zamir C, et al. Breastmilk hepatitis A virus RNA in
nursing mothers with acute hepatitis A virus infection. Breastfeed Med 2012;7:
3135.
12. Simsek Y, Isik B, Karaer A, et al. Fulminant hepatitis A infection in second
trimester of pregnancy requiring living-donor liver transplantation. J Obstet Gy-
naecol Res 2012;38(4):7458.

HEPATITIS B

13. Marion PL. Use of animal models to study hepatitis B viruses. Prog Med Virol
1988;35:4375.
588 Rac & Sheffield

14. Korba BE, Gowans EJ, Well FV, et al. Systemic distribution of woodchuck hepa-
titis virus in the tissues of experimentally infected woodchucks. Virology 1988;
165:17281.
15. Halpern MS, England JM, Deery JT, et al. Viral nucleic acid synthesis and antigen
accumulation in pancreas and kidney of Peking ducks infected with duck hepa-
titis B virus. Proc Natl Acad Sci U S A 1983;80:48659.
16. Barker LF, Maynard JE, Purcell RH, et al. Hepatitis B virus infection in chimpan-
zees: titration of subtypes. J Infect Dis 1975;132:4518.
17. Stevens CE, Beasley RP, Tsui J, et al. Vertical transmission of hepatitis B antigen
in Taiwan. N Engl J Med 1975;292:7714.
18. Dienstag JL. Hepatitis B virus infection. N Engl J Med 2008;359:1486500.
19. Kowdley KV, Wang CC, Welch S, et al. Prevalence of chronic hepatitis B among
foreign born persons living in the United States by country of origin. Hepatology
2012;56:42233.
20. World Health Organization. Media Centre. Hepatitis B. Fact sheet. Updated July
2013. Available at: http://www.who.int/mediacentre/factsheets/fs204/en/. Ac-
cessed April 4, 2014.
21. Bosch FX, Ribes J, Cleries R, et al. Epidemiology of hepatocellular carcinoma.
Clin Liver Dis 2005;9(2):191211.
22. Centers for Disease Control and Prevention. Hepatitis B information for health
professionals. Available at: http://www.cdc.gov/hepatitis/HBV/index.htm. Ac-
cessed April 4, 2014.
23. Connell LE, Salihu HM, Salemi JL, et al. Maternal hepatitis B and hepatitis C car-
rier status and perinatal outcomes. Liver Int 2011;31(8):116370.
24. Reddick KLB, Jhaveri R, Gandhi M, et al. Pregnancy outcomes associated with
viral hepatitis. J Viral Hepat 2011;18:3948.
25. Fan L, Owusu-Edusei K, Schillie S, et al. Cost-effectiveness of testing hepatitis B-
positive pregnant women for hepatitis B e antigen or viral load. Obstet Gynecol
2014;123:92937.
26. U.S. Preventive Services Task Force. Screening for hepatitis B infection in preg-
nancy, topic page. e2009. Available at: http://www.uspreventiveservicestaskforce.
org/uspstf/uspshepbpg.htm. Accessed April 27, 2014.
27. Dyson JK, Waller J, Turley A, et al. Hepatitis B in pregnancy. Frontline Gastroen-
terol 2014;5(2):1117.
28. Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy
to eliminate transmission of hepatitis B virus infection in the United States:
recommendations of the Advisory Committee on Immunization Practices
(ACIP) part 1: immunization of infants, children, and adolescents. Advisory
Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;
54(RR-16):131 [Erratum appears in MMWR Morb Mortal Wkly Rep 2006;55:
1589].
29. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. AASLD Practice Guide-
line Update. Hepatology 2009;50(3):136.
30. Patton H, Tran TT. Management of hepatitis B during pregnancy. Nat Rev Gastro-
enterol Hepatol 2014. http://dx.doi.org/10.1038/nrgastro.2014.30.
31. Lin HH, Lee TY, Chen DS, et al. Transplacental leakage of HBeAg-positive
maternal blood as the most likely route in causing intrauterine infection with hep-
atitis B virus. J Pediatr 1987;111:87781.
32. Pan CQ, Zou HB, Chen Y, et al. Cesarean section reduces perinatal transmission
of hepatitis B virus infection from hepatitis B surface antigen-positive women to
their infants. Clin Gastroenterol Hepatol 2013;11:134955.
 Viral Hepatitis During Pregnancy 589

33. Wong VC, Lee AK, Ip HM. Transmission of hepatitis B antigens from symptom free
carrier mothers to the fetus and the infant. Br J Obstet Gynaecol 1980;87:95865.
34. Mirochnik M, Thomas T, Capparelli E, et al. Antiretroviral concentrations in breast-
feeding infants of mothers receiving highly active antiretroviral therapy. Antimi-
crob Agents Chemother 2009;53:11706.
35. Sheffield JS, Hickman A, Tang J, et al. Efficacy of an accelerated hepatitis B
vaccination program during pregnancy. Obstet Gynecol 2011;117(5):11305.
36. Centers for Disease Control and Prevention. A comprehensive immunization strat-
egy to eliminate transmission of hepatitis B virus infection in the United States: rec-
ommendations of the Advisory Committee on Immunization Practices (ACIP) Part
II: immunization of adults. MMWR Recomm Rep 2006;55(RR-16):133.
37. Centers for Disease Control and Prevention. A comprehensive immunization
strategy to eliminate transmission of hepatitis B virus infection in the United
States: recommendations of the Advisory Committee on Immunization Practices
(ACIP) Part 1: immunization of infants, children, and adolescents. MMWR Re-
comm Rep 2005;54(RR-16):133.
38. United States Department of Health and Human Services. MMWR: a comprehen-
sive immunization strategy to eliminate transmission of hepatitis B virus infection
in the United States (online). Available at: http://www.cdc.gov/mmwr/preview/
mmwrhtml/rr5416a1.htm. Accessed May 10, 2014.
39. Shi Z, Yang Y, Ma L, et al. Lamivudine in late pregnancy to interrupt in utero trans-
mission of hepatitis B virus: A systematic review and meta-analysis. Obstet Gyne-
col 2010;116(1):14758 (Systematic review and/or Meta-analysis).
40. Deng M, Zhou X, Gao S, et al. The effects of telbivudine in late pregnancy to pre-
vent intrauterine transmission of the hepatitis B virus: a systematic review and
meta-analysis. Virol J 2012;9:185 (Systematic review and/or Meta-analysis).
41. Pan CQ, Duan ZP, Bhamidimarri KR, et al. An algorithm for risk assessment and
intervention of mother to child transmission of hepatitis B virus. Clin Gastroenterol
Hepatol 2012;10:4529.
42. Greenup AJ, Tan PK, Nguyen V, et al. Efficacy and safety of tenofovir diso-
proxil fumarate in pregnancy to prevent perinatal transmission of Hepatitis B
virus. J Hepatol 2014. http://dx.doi.org/10.1016/j.jhep.2014.04.038. pii:S0168
8278(14)00301-8.
43. Nayeri UA, Werner EF, Han CS, et al. Antenatal lamivudine to reduce perinatal
hepatitis B transmission: a cost-effectiveness analysis. Am J Obstet Gynecol
2012;207:231.e17.
44. Zou H, Chen Y, Duan Z, et al. Virologic factors associated with failure to passive-
active immunoprophylaxis in infants born to HBsAg-positive mothers. J Viral
Hepat 2012;19:e1825.
45. Alexander JM, Ramus R, Jackson G, et al. Risk of hepatitis B transmission after
amniocentesis if chronic hepatitis B carriers. Infect Dis Obstet Gynecol 1999;7(6):
2836.
46. Yi W, Pan CQ, Hao J, et al. Risk of vertical transmission of hepatitis B after amnio-
centesis in HBs antigen-positive mothers. J Hepatol 2014;60:5239.

HEPATITIS C

47. Lemons SM, Walker CM. Hepatitis C virus. In: Knipe DM, Howley PM, editors. Fields
virology. 5th edition. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 91.
48. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C
virus infection. Nat Rev Immunol 2005;5(3):21529.
590 Rac & Sheffield

49. World Health Organization. Guidelines for the screening, care and treatment of
persons with hepatitis C infection. 2014. Available at: http://apps.who.int/iris/
bitstream/10665/111747/1/9789241548755_eng.pdf?ua=1. Accessed May 20,
2014.
50. Centers for Disease Control and Prevention. Hepatitis C information for health
professionals. Available at: http://www.cdc.gov/hepatitis/HCV/Index.htm. Ac-
cessed May 20, 2014.
51. McMenamin MB, Jackson A, Lambert J, et al. Obstetric management of hepatitis
C-positive mothers: analysis of vertical transmission in 559 mother-infant pairs.
Am J Obstet Gynecol 2008;199:315.e5.
52. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in pa-
tients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC
groups. Lancet 1997;349(9055):82532.
53. Machicao VI, Bonatti H, Krishna M, et al. Donor age affects fibrosis progression
and graft survival after liver transplantation for hepatitis C. Transplantation 2004;
77(1):8492.
54. Thein HH, Yi Q, Dore GJ, et al. Estimation of stage-specific fibrosis progression
rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression.
Hepatology 2008;48(2):41831 (Systematic review and/or Meta-analysis).
55. Berkely EM, Leslie KK, Arora S, et al. Chronic hepatitis C in pregnancy. Obstet
Gynecol 2008;112(2 part 1):30410.
56. Pergram SA, Wang CC, Gardella CM, et al. Pregnancy complications associated
with hepatitis C: data from a 2003-2005 Washington state birth cohort. Am J
Obstet Gynecol 2008;199:38.e19.
57. Salemi JL, Whiteman VE, August EM, et al. Maternal hepatitis B and hepatitis C
infection and neonatal neurological outcomes. J Viral Hepat 2014. http://dx.doi.
org/10.1111/jvh.12250.
58. Mast EE, Hwang LY, Seto DS, et al. Risk factors for perinatal transmission of hep-
atitis C virus (HCV) and the natural history of HCV infection acquired in infancy.
J Infect Dis 2005;192:18809.
59. Bevilacqua A, Fabris A, Floreano P, et al. Genetic factors in mother-to-child trans-
mission of HCV infection. Virology 2009;390:6470.
60. Airoldi J, Berghella V. Hepatitis C and pregnancy. Obstet Gynecol Surv 2006;
61(10):66672.
61. Chutaputti A. Adverse effects and other safety aspects of the hepatitis C antivi-
rals. J Gastroenterol Hepatol 2000;15:E15663.
62. De Clercq E. The design of drugs for HIV and HCV. Nat Rev Drug Discov 2007;
6(12):100118.
63. Schlutter J. Therapeutics: new drugs hit the target. Nature 2011;474(7350):S57.
64. Ghamar Chehreh ME, Tabatabaei SV, Khazanehdari S, et al. Effect of cesarean
section on the risk of perinatal transmission of hepatitis C virus from HCV-
RNA1/HIV mothers: a meta-analysis. Arch Gynecol Obstet 2011;283:25560.
65. Lopez M, Coll O. Chronic viral infections and invasive procedures: risk of vertical
transmission and current recommendations. Fetal Diagn Ther 2010;28:18.
66. Murakami J, Nagata I, Iitsuka T, et al. Risk factors for mother-to-child transmission
of hepatitis C virus: Maternal high viral load and fetal exposure in the birth canal.
Hepatol Res 2012;42:64857.
67. Cottrell EB, Chou R, Wasson N, et al. Reducing risk for mother-to-infant trans-
mission of hepatitis C virus: a systematic review for the U.S. Preventive Services
Task Force. Ann Intern Med 2013;158:10913 (Systematic review and/or
Meta-analysis).
 Viral Hepatitis During Pregnancy 591

68. Mok J, Pembrey L, Tovo PA, et al. When does mother to child transmission of hep-
atitis C virus occur? Arch Dis Child Fetal Neonatal Ed 2005;90:F15660.
69. European Paediatric Hepatitis C Virus Network. A significant sex-but not elective
cesarean section-effect on mother-to-child transmission of hepatitis C virus infec-
tion. J Infect Dis 2005;192:18729.

HEPATITIS D

70. Centers for Disease Control and Prevention. Division of Viral Hepatitis. Hepatitis D
information for health professionals. Available at: www.cdc.gov/hepatitis/HDV/.
Accessed May 5, 14.
71. Price J. An update on hepatitis B, D and E viruses. Top Antivir Med 2014;21(5):15763.
72. World Health Organization. Global alert and response. Hepatitis D virus. Avail-
able at: http://www.who.int/csr/disease/hepatitis/whocdscsrncs20011/en/index3.
html. Accessed May 14, 2014.
73. Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. Lancet 2011;
378(9785):7385.
74. Mansour W, Malick FZ, Sidiya A, et al. Prevalence, risk factors, and molecular
epidemiology of hepatitis B and hepatitis delta virus in pregnancy women and
in patients in Mauritania. J Med Virol 2012;84(8):118698.
75. Makuwa M, Caron M, Souqiuere S, et al. Prevalence and genetic diversity of hep-
atitis B and delta viruses in pregnant women in Gabon: molecular evidence that
hepatitis delta virus clade 8 originates from and is endemic in central Africa.
J Clin Microbiol 2008;46(2):7546.
76. Drobeniuc J, Hutin YJ, Harpaz R, et al. Prevalence of hepatitis B, C, and D virus
infections among children and pregnant women in Moldova: additional evidence
supporting the need for routine hepatitis B vaccination of infants. Epidemiol Infect
1999;123:4637.
77. Cross TJ, Rizzi P, Horner M, et al. The increasing prevalence of hepatitis delta
virus (HDV) infection in South London. J Med Virol 2008;80:27782.

HEPATITIS E

78. Wedemeyer J, Pischke S, Manns M. Pathogenesis and treatment of hepatitis E

virus infection. Gastroenterology 2012;142:138897.
79. Purcell RH, Emerson SU. Hepatitis E: emerging awareness of an old disease.
J Hepatol 2008;48:494503.
80. Centers for Disease Control and Prevention. Division of viral hepatitis. Hepatitis E
information for health professionals. Available at: http://www.cdc.gov/hepatitis/
HEV/index.htm. Accessed May 14, 2014.
81. World Health Organization. Hepatitis E fact sheet, updated July 2013. Available at:
http://www.who.int/mediacentre/factsheets/fs280/en/. Accessed May 24, 2014.
82. Niet de A, Zaaijer HL, Ten Berge I, et al. Chronic hepatitis E after solid organ
transplantation. Neth J Med 2012;70:2616.
83. Labrique AB, Sikder SS, Krain LJ, et al. Hepatitis e, a vaccine-preventable cause
of maternal deaths. Emerg Infect Dis 2012;18(9):14014.
84. Scobie L, Dalton HR. Review. Hepatitis E: source and route of infection, clinical
manifestations and new developments. J Viral Hepat 2013;20:111.
85. Kamar N, Bendall RP, Peron JM, et al. Hepatitis E virus-induced neurologic dis-
orders. Emerg Infect Dis 2011;17:1739.
86. Kamar N, Weclawski H, Guibeau-Frugier C, et al. Hepatitis E virus and the kidney
in solid-organ transplant patients. Transplantation 2012;93(6):61723.
592 Rac & Sheffield

87. Feagins AR, Opriessing R, Guenette DK, et al. Detection and characterization of
infectious Hepatitis E virus from commercial pig livers sold in local grocery stores
in the USA. J Gen Virol 2007;88(Pt 3):9127.
88. Krain LJ, Atwell JE, Nelson KE, et al. Review article: fetal and neonatal health con-
sequences of vertically transmitted hepatitis E virus infection. Am J Trop Med Hyg
2014;90(2):36570.
89. Khuroo MS, Kamili S, Khuroo MS. Clinical course and duration of viremia in verti-
cally transmitted hepatitis E virus (HEV) infection in babies born to HEV-infected
mothers. J Viral Hepat 2009;16(7):51923.
90. Rein DB, Stevens G, Theaker J, et al. The global burden of hepatitis E virus. Hep-
atology 2011;55(4):98897.
91. Sultana R, Humayun S. Fetomaternal outcome in acute hepatitis e. J Coll Physi-
cians Surg Pak 2014;24(2):12730.
92. Bose PD, Das BC, Hazam RK, et al. Evidence of extrahepatic replication of hep-
atitis E virus in human placenta. J Gen Virol 2014. http://dx.doi.org/10.1099/vir.0.
063602-0.
93. Mehta A, Singla A, Rajaram S. Prognostic factors for fulminant viral hepatitis in
pregnancy. Int J Gynaecol Obstet 2012;118:1725.
94. Borkakoti J, Hazam RK, Mohammad A, et al. Does high viral load of hepatitis E
virus influence the severity and prognosis of acute liver failure during pregnancy?
J Med Virol 2013;85:6206.
95. Salam GD, Kumar A, Kar P, et al. Serum tumor necrosis factor-alpha level in hep-
atitis E virus-related acute viral hepatitis and fulminant hepatic failure in preg-
nancy women. Hepatol Res 2013;43(8):82635.
96. Devi SG, Kumar A, Kar P, et al. Association of pregnancy outcome with cytokine
gene polymorphisms in HEV infection during pregnancy. J Med Virol 2014. http://
dx.doi.org/10.1002/jmv.23925.
97. Renou C, Gobert V, Locher C, et al. Prospective study of hepatitis E virus infection
among pregnant women in France. Virol J 2014;11(1):68.